Open Access

Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: Meta-analysis and systematic review

  • Authors:
    • Da‑Ping Yu
    • Xu Cheng
    • Zhi‑Dong Liu
    • Shao‑Fa Xu
  • View Affiliations

  • Published online on: May 29, 2017     https://doi.org/10.3892/ol.2017.6274
  • Pages: 1568-1580
  • Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer is the most commonly diagnosed cancer among men and it is the third ranked in women. There are two major types of lung cancer, namely, small cell lung cancer (SCLC), which accounts for ~20% of the cases, and non‑small cell lung cancer (NSCLC), which is the most common. Chemotherapy and chemoradiotherapy have been used as the first‑line therapies but suffer from lack of efficacy and also of several toxic adverse effects. Immunotherapeutic approaches including tumor antigen vaccination, monoclonal antibodies targeting checkpoint pathways and also activated immune cells are being developed and have been shown to be effective in treating NSCLC. Despite their promise, efficacy of several immunotherapies has not been consistent. We undertook this meta‑analysis study to analyze results from clinical trials that compared efficacy and safety of immunotherapies with placebo or chemotherapy/radiotherapy in improving overall survival (OS) and progression‑free survival (PFS) of NSCLC patients. Various databases were searched to identify randomized clinical studies examining the efficacy and safety of antibody‑ and vaccine‑based immunotherapies in NSCLC patients in comparison to chemotherapy or chemoradiotherapy or placebo. Effects on OS and PFS and also adverse events have been compared. In accordance with the selection criteria, a total of 13 studies with 3,513 patients in immunotherapy and 3,072 patients in chemotherapy/placebo, were selected. PFS (odds ratio 1.81, 95% CI 1.36, 2.42; P<0.0001) and OS (P<0.0001) are found to be greatly improved by immunotherapies. Immunotherapy of NSCLC patients was also found to prevent several adverse effects and to improve daily living ability of the patients. The present meta‑analysis strongly suggests that immunotherapy improves OS and PFS of patients with NSCLC.

Introduction

According to worldwide cancer statistics (Globocan 2012), lung cancer is the most commonly diagnosed cancer among men, and in women it is the third most commonly diagnosed (1). Approximately 2 million new cases of lung cancer and 1.5 million lung cancer related deaths are recorded each year (2). Mortality due to lung cancer is estimated to increase up to 10 million per year in another 15 years (3). There are two major types of lung cancer, viz., small cell lung cancer (SCLC), which is less common accounting for ~20% of the cancer cases, and non-small cell lung cancer (NSCLC), which is the most common, accounting for almost 85% of lung cancer cases (4). Despite the high incidence and associated mortality, the available treatment options and prognosis for NSCLC are not satisfactory. In a recent meta-analysis, we showed that exercise at medium to high level intensity is associated with lower risk of lung cancer, both in men and women, indicating the lifestyle-based benefits for reducing lung cancer risk (5). Platinum-doublet chemotherapy, which is the standard first-line therapy, has been shown to yield objective responses with a median overall survival (OS) of 8–10 months in approximately 30–40% of patients with NSCLC and there are significant safety issues (6). Considering that the efficacy of platinum-based therapies is dependent on the mutational/single nucleotide polymorphisms (SNP) status of the components of DNA-damage repair systems available in the target cancer cells, there can be significant individual differences in treatment responses. Thus, we showed earlier that the SNPs XRCC1Arg399Gln and XPG His46His are associated with significantly better treatment response in NSCLC patients to platinum-based chemotherapy (7). On the other hand, tyrosine kinase inhibitors (e.g., gefitinib, erlotinib, and afatinib) are found to be more effective with nearly 65% response rate and a median OS of 24–36 months in NCLSC patients with EGFR mutations (8). In addition to chemotherapy and chemoradiotherapy, immunological approaches have been shown to be effective in treating various cancers, including NSCLC. Significant advances have been made in the last 3 years in the development of immunotherapies for NSCLC. Immunotherapies include tumor antigen vaccination, monoclonal antibodies targeting checkpoint pathways and also activated immune cells (810). Several recent studies have shown the efficacy of immunotherapies against advanced stage NSCLC patients (1012). Despite the promise of several immunotherapies, their efficacy has not been consistent as noted in the phase III FORTIS trial (13). Response to immunotherapies can also be dependent on many other factors, such as chemokines that influence immune cell function. Thus, we reported earlier that polymorphism (−2518A/G) in the gene coding for monocyte chemoattractant protein-1 (MCP-1) is associated with elevated risk for NSCLC. MCP-1 is known to be a tumor suppressor via pathways involving T-lymphocytes or independent of lymphocytes (14). Similarly, we also noted that the frequencies of polymorphisms in the human leukocyte antigen (HLA) system, which is involved in the regulation of immune response, HLA-A*0201, A*2601, B*1518, B*3802, DRB1*0401, DRB1*0402, and DRB1*1201 are higher in the lung cancer patients than healthy controls (15), and affect the tumor immunity.

An earlier meta-analysis of 12 randomized controlled trials of immunotherapies indicated a beneficial effect on OS with few adverse effects (6). However, in this analysis, 3 monoclonal antibody (Mab)-based trials with cetuximab (targets EGFR) and one trial with trastuzumab (targets HER2) as NSCLC Mab therapy subgroup, whereas these actually are related to the growth factors and not immune system. A recent meta-analysis of several clinical trials of immunotherapies, including therapeutic vaccines and immune checkpoint inhibitors showed that immunotherapies are well tolerated in advanced NSLSC patients and improve OS and that specific antitumor immune response simulating agents are more efficacious than immunomodulatory type agents (16). A comparison of tumor vaccine-based therapies with cellular immunotherapies, in a meta-analysis revealed that cellular immunotherapies are more effective in improving OS and progression-free survival (PFS) in NSCLC patients (12). However, in many of these meta-analyses, the number of included studies and the total number of patients was lower and also, as mentioned above, inclusion of unrelated therapies could have complicated the outcomes and conclusions. Also, discordant results were seen in certain clinical trials using immunotherapies against NSCLC as the promising phase II study results were not observed in phase III study, leading to premature termination of the clinical trials, questioning the efficacy of immunotherapy (17). We have now conducted a meta-analysis of 13 clinical trials assessing the efficacy and safety of Mab therapies directed against tumor antigens and tumor antigen-based vaccination therapies, as compared to chemotherapy/chemoradiotherapy in NSCLC patients.

In the present meta-analysis, we analyzed results from clinical trial studies that simultaneously compared immunotherapies with placebo or chemotherapy/radiotherapy to assess the beneficial effects of immunotherapies collectively or separately in improving OS and PFS of NSCLC patients. Besides efficacy, we also examined if immunotherapies are better in terms of safety, by looking at the treatment-related adverse effects.

Materials and methods

Criteria for considering studies for this review

Randomized controlled phase II and III clinical trials on patients with NSCLC at stage III and IV, with histological confirmation are included in this analysis. In these studies, immunotherapies were administered to patients along with chemotherapy or as monotherapy and the treatment effects were compared to a control group of patients, who received either chemotherapy alone or placebo. For the present meta-analysis, we have included only vaccine-based and Mab-based immunotherapy studies and not the immune cell-based adoptive immunotherapy clinical trials. Studies that did not include proper controls were excluded from this meta-analysis. Most of the patients in the included studies had Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (18). Patients were excluded if they were on concurrent systemic steroids, with metastases in bone requiring immediate therapy, uncontrolled pleural effusions, serious non-malignant disease or previous malignancies or if they had myocardial infarction or other cardiovascular disease in the 6-month period prior to study. Approximately half of the included studies were open-label, whereas the remaining are double-blind studies.

Search methods

Literature search was completed on 10 January 2017 and publications that included complete relevant information and data were collected. Following databases were searched: PubMed, Google Scholar, Scopus, Web of Science and Cochrane Central Register. Search MeSH terms included lung cancer, NSCLC, immunotherapy, vaccine therapy for NSCLC, vaccination for NSCLC, OS, clinical trials, PFS and Mab therapy. All the relevant publications only in English language were collected and were initially screened at the title and abstract level. Only clinical trials at phase II and III level were included in this analysis. Full reports and supplemental information files were retrieved as per the relevance of the selected study.

Data collection and analysis and quality assessment

All the authors of this meta-analysis participated in the screening of collected publications and data extraction. Data including patient baseline characteristics such as age, sex, description and dosages of the administered treatment, tumor histology, and disease stage, and treatment primary endpoint measurements (PFS events, OS) and treatment related adverse effects were collected, by filling out a pre-defined data collection form, from each included study. OS, which was defined as the time from randomization to censor or death due to any cause, was mostly reported as median months and for the purposes of meta-analysis, these values were converted to mean ± SD. The period from randomization of patients to the progression of disease (or death if it occurred first), during the study duration, as ascertained and documented by the study investigators, was defined as PFS. Treatment related adverse effects were evaluated to assess the safety of immunotherapy procedure, and the adverse events (scoring grade ≥3) reported in more than two clinical trials, as the number of patients were collected. These include both hematological and non-hematological effects. Hematological events recorded were anemia, neutropenia, thrombocytopenia and the non-hematological events include fatigue, vomiting, abdominal pain, fever, nausea, and anorexia/loss of appetite.

Statistical analysis

Statistical analyses were conducted using the methods described by the Cochrane Collaboration guidelines for meta-analysis, using Review Manager (RevMan) version 5.3 software (the Cochrane Collaboration). As mentioned above, OS was mostly reported as median months and lower and upper limits of the range and for the purposes of meta-analysis, these values were converted to mean ± SD. Number of PFS events, were not given directly, was deduced from the PFS plots in the individual trials. The effect of immunotherapy on PFS and each of the adverse events were analyzed by Mantel-Haenszel statistics, odds ratios (OR) in the random-effect model, at 95% confidence intervals (CI). The effect of immunotherapy on OS was assessed by mean difference analyses in inverse variance (IV) fixed mode at 95% confidence intervals. Sensitivity analysis was performed by excluding one study at a time and also by removing study with highest weightage, among the included data to examine influence of bias on the deduced statistical significance and interpretation. Risk ratios were calculated for adverse events and also for PFS at 95% confidence intervals.

Results

Search from all the databases yielded 12,338 studies, which contained the search MeSH terms either in the title or in the abstract. Exclusion of studies was done through the participation of all authors, who read the abstracts and a collective decision was adopted. A total of 13 studies (11,1929) were identified on the basis of relevancy and inclusion/exclusion criteria and completeness of the data in the study (Fig. 1). As immunotherapy of NSCLC is a recently developed treatment approach, all the studies identified are published after 2011. The total number of patients in all the included studies was 6,585 and the number of patients who received immunotherapy was 3,513, whereas the control group patients who received chemotherapy or placebo were 3,072 (Fig. 1).

Patient characteristics

The demographic and baseline characteristics of patients in the included studies are given in Table I. Average age of the patients in both immunotherapy and control groups was ~62 years. Nearly 64.3% of the patients who received immunotherapy were males while in control chemotherapy group 62.9% were males. Tumors were of adenocarcinoma type, by histological examination in nearly two-thirds of the patients in both immunotherapy group (n=2,155) and in control group (n=2,009) and next major histological type was squamous cell carcinoma (Table I). ECOG performance status, which is an indicator of the patient's daily living ability and the progress of disease, is predominantly 0 or 1 for most of the included patients, in both immunotherapy and chemotherapy/placebo groups (18). Majority of the patients are restricted for strenuous physical activity, even though they could carry out light and sedentary work.

Table I.

Baseline characteristics of patients included in the meta-analysis.

Table I.

Baseline characteristics of patients included in the meta-analysis.

A, Immunotherapy
ECOG status (no. of patients)Histology type (n)
Author (ref.) yearStudy typeType of immunotherapyNo. of patientsAge, yearsMales, %Immunotherapy dosage012AdSq
Quoix et al (19) 2011Controlled multicenter phase 2BTG4010 genetic vaccine (targets tumor MUC1)7458.571.6108 pfu; cisp75 mg/m2 on day 1; gem 1.25 g/m2 on day 1, 8; every 3 weeks × 6 cycles205314719
Lynch et al (20) 2012Randomized, double-blind phase 2BIpilimumab (anti-cytotoxic T-cell lymphocyte-4 Mab)70597610 mg/kg Ipilimumab; pacli 175 mg/m2; carbo AUC 6; i.v. dosing every 3 weeks × 6 cycles1951 3521
Borghaei et al (21) 2015Randomized, open-label phase 3Nivolumab human IgG4 PD-1 immune checkpoint inhibitor Mab29261523 mg/kg, every 2 weeks; for 13.2 months minimum84208 2687
Brahmer et al (11) 2015Randomized, open-label, multicenter, phase 3Nivolumab (IgG4 PD.1 Mab)13562823 mg/kg, every 2 weeks27106
Fehrenbacher et al (22) 2016Multicenter, open-label, randomized phase 2Atezolizumab (anti-PD-L1 Mab)1446265Atezolizumab 1.2 g fixed, i.v., on day 1, every 3 weeks4696 9549
Herbst et al (23) 2016Multicenter, randomized, open-label, phase 2/3Pembrolizumab (MK-3475; human IgG4 PD-1 Mab)3446362Pembrolizumab, 2 mg/kg, every 3 weeks112229324076
Herbst et al (23) 2016Multicenter, randomized, open-label, phase 2/3Pembrolizumab (MK-3475; human IgG4 PD-1 Mab)3466362Pembrolizumab, 10 mg/kg, every 3 weeks120225124480
Quoix et al (24) 2016Randomized, double-blind multicenter, controlled phase 2b/3TG4010 genetic vaccine1116365108 pfu; every week for 6 weeks then every 3 weeks; cisp 75mg/m2 on day 1; gem 1.25g/m2 on day 1, 83377 9513
Reck et al (25) 2016Open-label, multicenter, phase 3Pembrolizumab (MK-3475; human IgG4 PD-1 Mab)15464.559.7Pembrolizumab, 200 mg every 3 weeks, 35 cycles5499 12529
Rittmeyer et al (26) 2017Open-label, multicenter randomized controlled phase 3Atezolizumab (Anti-PD-L1 Mab)4256361atezolizumab 1.2 g fixed, i.v., on day 1, every 3 weeks155270 313112
Butts et al (27) 2014START randomized, double-blind, multicenter phase 3Tecemotide vaccine (MUC1-antigen-specific immunotherapy)8296168Subcutaneous tecemotide (806 µg lipopeptide) + lipid-A+ liposome forming lipids398427 289401
Herbst et al (28) 2011Double-blind, multicenter placebo-controlled phase 3Bevacizumab (recombinant, anti-vascular endothelial growth factor Mab)3196554Bevacizumab at 15 mg/kg, i.v., on day 1, every 3 weeks + erlotinib 150 mg/day1291662324223
Giaccone et al (29) 2015Phase 3 studyBelagenpumatucel-L (whole tumor cell vaccine, of NSCLC) cells, transfected with a human TGF-β2-antisense vector27061.5582.5×107 total cells were injected intradermally119139716265

B, Chemotherapy/placebo

ECOG status (no. of patients)Histology type (n)


Author (ref.) yearStudy typeType of chemotherapyNo. of patientsAge, yearsMales, %Chemotherapy dosage012AdSq

Quoix et al (19) 2011Controlled multicenter phase 2BCisplatin + gemcitabine7458.573Cisp 75 mg/m2 on day 1; gem 1.25 g/m2 on day 1, 8; every 3 weeks × 6 cycles20  5405511
Lynch et al (20) 2012Randomized double-blind phase 2BPaclitaxel + carboplatin666274Pacli 175 mg/m2; carbo AUC 6; i.v. dosing every 3 weeks × 6 cycles15  51 3815
Borghaei et al (21) 2015Randomized open-label, phase 3Docetaxel2906458Docetaxel 75 mg/m2 every 3 weeks; for 13.2 months minimum95194 2737
Brahmer et al (11) 2015Randomized open-label, multicenter phase 3Docetaxel1376471Docetaxel 75 mg/m2 every 3 weeks37100
Fehrenbacher et al (22) 2016Multicenter, open-label, randomized phase 2Docetaxel1436253Docetaxel 75 mg/m2 on day 1, every 3 weeks45  97 9548
Herbst et al (23) 2016Multicenter, randomized, open-label, phase 2/3Docetaxel3436261Docetaxel 75 mg/m2 on day 1, every 3 weeks116224124066
Quoix et al (24) 2016Randomized, double-blind multicenter, controlled phase 2b/3Cisplatin + gemcitabine1115963Cisp 75 mg/m2 on day 1; gem 1.25 g/m2 1, every 3 weeks + on day 1, 8; every 3 weeks × 6 cycles  35  76   9013
Reck et al (25) 2016Open-label, multicenter, phase 3 Carboplatin/cisplatin/paclitaxel/gemcitabine1516662.9Varying dosages  53  98 12427
Rittmeyer et al (26) 2017Open-label, multicenter randomized controlled phase 3Docetaxel4256461Docetaxel 75 mg/m2, on day 1, every 3 weeks160165 315110
Butts et al (27) 2014START randomized, double-blind multicenter, phase 3Placebo41061.568Liposome forming lipids167239 163171
Herbst et al (28) 2011Double-blind, multicenter, placebo-controlled, phase 3 trialErlotinib (EGFR inhibitor)31764.854Erlotinib 150 mg/day12117620  9017
Giaccone et al (29) 2015Phase 3 studyPlacebo26260.5580.15% intralipid130119614181

[i] ECOG status, Eastern Cooperative Oncology Group performance status; Ad, adenocarcinoma; Sq, squamous cell carcinoma; pfu, plaque forming units; cisp, cisplatin; gem, gemcitabine; carbo, carboplatin; pacli, paclitaxel; Mab, monoclonal antibody.

In the present meta-analysis study, only antibody-based and vaccine-based immunotherapies are included. Cellular therapy studies were not included as many of these studies are at early phase I stage. Out of the 13 studies, nine were antibody-based immunotherapies, while the remaining four were vaccine-based. Antibody therapies included ipilimu-mab, an anti-cytotoxic T-cell lymphocyte-4 Mab (20); nivolumab, a human IgG4 PD-1 immune-checkpoint-inhibitor Mab (11,21); atezolizumab, another anti-PD-L1 Mab (22,26); pembrolizumab, also known as MK-3475, a human IgG4 PD-1 Mab (23,25); and bevacizumab, a recombinant, anti-vascular endothelial growth factor Mab (28). Vaccine-based immunotherapies included TG4010 genetic vaccine, which is a suspension of a recombinant modified vaccinia virus strain Ankara (MVA), coding for the MUC1 tumor-associated antigen and interleukin-2 (19,24); tecemotide (L-BLP25), a tumor associated MUC1 antigen-specific immunotherapy, that is capable of inducing a T-cell response to MUC1 (27) and belagenpumatucel-L, an allogeneic whole tumor cell vaccine consisting of four pCHEK/HBA2 (human transforming growth factor-β2-antisense vector)-transfected NSCLC cell lines (29). Immunotherapy dosages and chemotherapy dosages are shown in Table I. Dosage of antibodies varied depending on the study and antibody used. Thus, ipilimumab was given at 10 mg/kg as four doses plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin, intravenously every 3 weeks for up to 18 weeks (20). Nivolumab was given at 3 mg/kg, every 2 weeks, for 11 to 13.2 months (11,21). Atezolizumab was given at 1.2 g fixed dose, intravenously on day 1, every 3 weeks, for at least 9 months (22,26). Pembrolizumab was given at 2 mg or 10 mg/kg, every 3 weeks for 24 months (23) or at 200 mg every 3 weeks in 35 cycles (25). Bevacizumab was given at 15 mg/kg, intravenously on day 1, every 3 weeks + erlotinib 150 mg/day (28). TG4010 genetic vaccine was administered at 108 pfu along with cisplatin 75 mg/m2 on day 1; gemcitabine 1.25 g/m2 on day 1 and 8, every 3 weeks in 6 cycles (19,24). Tecemotide was administered subcutaneously, as 806 µg lipopeptide with lipid-A and liposome forming lipids (27). Belagenpumatucel-L was given intradermally at a dose of 2.5×107 total cells (29). Chemotherapy generally included carboplatin, paclitaxel, docetaxel, cisplatin and gemcitabine. In one study (28), EGFR inhibitor, erlotinib was used as chemotherapy agent in control group patients. Where chemotherapy was not the regimen for control group patients, vehicle (used for immunotherapy) placebo (intralipid or liposome forming lipids) was given.

Effect of immunotherapy on PFS and OS

In pooled OR analysis (Mantel-Haenszel, random) of both types of immunotherapies, PFS was found to be significantly increased (Fig. 2A) in a higher number of patients as compared to chemotherapy/placebo control group (OR 1.81, 95% CI 1.36, 2.42; P<0.0001). Further separate analysis of antibody therapy also revealed a significant beneficial effect on PFS in antibody receiving patients (Fig. 2B) as compared to control group (OR 2.05, 95% CI 1.42, 2.94; P<0.0001). Even though the vaccine therapy-receiving patients also showed better PFS compared to control group (Fig. 2C), the statistical significance (OR 1.31, 95% CI 1.05, 1.63; P<0.01) was not as high as in the case of antibody therapy. These results are in accordance with earlier results of a pooled analysis of the beneficial effects of immunotherapies (12). Similar results were obtained by risk ratio (RR) analysis (Table II). Thus, RR for both types of immunotherapies was 1.297 (95% CI 1.211, 1.389; P=0) and for Mab therapy RR was 1.335 (95% CI 1.222, 1.458; P=0). But RR for vaccine therapy was 1.063 and was not significant (95% CI 0.96, 1.176; P=0.239).

Table II.

Risk ratio analysis of PFS in antibody-based and vaccine-based immunotherapy groups vs. corresponding chemotherapy/placebo groups.

Table II.

Risk ratio analysis of PFS in antibody-based and vaccine-based immunotherapy groups vs. corresponding chemotherapy/placebo groups.

Immunotherapy Chemotherapy/placebo 95% CI



PFSEventsNon-eventsTotalEventsNon-eventsTotalRisk ratioLowerUpperP-value
PFS (for all immunotherapy)1,3291,9143,2438881,9222,8101.29681.21121.38850
PFS (for antibody-based therapy)8021,4272,2295971,6182,2151.33491.22231.45790
PFS (for vaccine-based therapy)5274871,0142913045951.06270.96041.17590.2392

[i] PFS, progression-free survival; CI, confidence interval.

OS was significantly enhanced by both the immunotherapies as compared to chemotherapy/placebo controls (Fig. 3A), as revealed by mean difference analysis in IV fixed mode (P<0.00001). Unlike in the case of PFS, OS was greatly improved by both antibody-based therapy (Fig. 3B; P<0.00001) and vaccine-based therapy (Fig. 3C; P<0.00001). These results are in agreement with earlier findings showing the beneficial effects of immunotherapies on OS (12,16).

Effect of immunotherapies on treatment related adverse effects

Earlier studies indicated that hematological adverse effects were relatively lower in patients treated with immune check point inhibitors whereas in vaccine treated patients these effects were observed often (16). In the present meta-analysis (OR, Mantel-Haenszel, random), we observed that among the hematological adverse effects (Fig. 4), anemia (Fig. 4A; OR 0.27, 95% CI 0.15, 0.49; P<0.0001) and neutropenia (Fig. 4B; OR 0.09, 95% CI 0.02, 0.35; P=0.0004) are significantly lower in the immunotherapy-receiving patients (Table III). However, events of thrombocytopenia (Fig. 4C; OR 0.68, 95% CI 0.31, 1.51; P=0.34) are not different compared to chemotherapy/placebo control group. Thrombocytopenia events were reported only in approximately half of the included studies, unlike anemia and neutropenia. It has been shown earlier that thrombocytopenia events are similar or even more common in patients treated with immunomodulatory therapy (16). Among the non-hematological adverse effects, neither abdominal pain nor loss of appetite/anorexia was found to be different in the immunotherapy group (Fig. 5A and B). However, fatigue, which is a commonly seen adverse effect appeared to be much less common in the immunotherapy group, as compared to the control chemotherapy/placebo group (Fig. 5C; OR 0.67, 95% CI 0.52, 0.86; P<0.001). A closer look at the data indicated that the number of patients with fatigue are much less in the antibody treated group, compared to their controls, whereas the events seems to be higher in the vaccine treated group. Other adverse effects including nausea, fever and vomiting are not much different in the immunotherapy group (Fig. 6).

Table III.

Risk ratio analysis of adverse effects in immunotherapy vs. chemotherapy/placebo groups.

Table III.

Risk ratio analysis of adverse effects in immunotherapy vs. chemotherapy/placebo groups.

Immunotherapy Chemotherapy/placebo 95% CI



Event measuredEventsNon-eventsTotalEventsNon-eventsTotalRisk ratioLowerUpperP-value
Anemia2701,9942,2645331,6002,1330.47730.41740.54570
Neutropenia1552,1092,2644721,6612,1330.30940.26060.36730
Thrombocytopenia  99   9921,091106   9091,0150.86890.66981.12720.2899
Abdominal pain  511,2881,339  451,1591,2041.01910.68771.510.925
Nausea5443,0143,5585982,2742,8720.73430.6610.81580
Fatigue7662,7923,5588412,0312,8720.73520.67550.80020
Vomiting2062,0582,2642651,8682,1330.73240.61650.870.0004
Anorexia5532,9343,4874862,3212,8070.9160.81951.02380.1221
Fever2302,1232,3531842,0392,2231.18090.98151.42090.0781

[i] CI, confidence interval.

Sensitivity analysis

In order to assess the robustness and to eliminate bias in the results, we re-analyzed the PFS and OS data by excluding individual trials with highest or lowest weightage. Such analysis did not qualitatively alter the obtained results and conclusions (data not elaborated). The OS benefits were still noted by immunotherapy over the chemotherapy/placebo controls. These conclusions are in agreement with earlier study (16), indicating that the benefits of immunotherapy are real and reproducible.

Discussion

Chemotherapy and chemoradiotherapy are the first-line therapy for several cancers including NSCLC. Even though objective responses have been noted with many of these therapies, the efficacy is not observed in all the patients. Tyrosine kinase receptor inhibitors showed better effects on OS and PFS but due to resistance, their efficacy is lost and disease progression takes place. A better understanding of immune mechanisms and host antitumor responses led to the identification of potential therapeutic opportunities employing the components of immune system. These include different types of immunotherapies based on the use of monoclonal antibodies against tumor specific antigens and immune checkpoint pathways, immunomodulators, vaccination against tumor antigens and activated immune cells that attack tumors (8,30). In the present meta-analysis, we examined the effectiveness of immunotherapies in improving PFS and OS. A total of 13 multicenter international phase II and III clinical trials addressing the efficacy of antibody therapies and vaccine therapies for treating NSCLC patients are included in this analysis. Among these studies, 9 were Mab-based therapies targeting different antigens and 4 were vaccine-based, with different immunogens. The immune check point pathway targets of the employed Mabs were programmed death-1 (PD1), programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Vaccine therapies were targeting the MUC1 tumor-associated antigen and using NSCLC cells transfected with human transforming growth factor-β2-antisense vector.

In line with other studies, we observed that immunotherapies offer better efficacy in terms of improved PFS and OS. Surprisingly, we observed that Mab therapies are more effective in improving PFS than the vaccine-based therapies (25,26,28). This can be because of the less number of vaccine-based studies and less number of patients in this analysis. An earlier meta-analysis indicated that immunotherapies have relatively stronger effect in improving PFS in low-stage NSCLC than in high-stage NSCLC patients (12). It was also observed that tumor histology is not related to disease progression. Combination of chemotherapy with immunotherapy has been proposed to have synergistic effect in inducing tumor cell death and by disrupting the immune evasion pathways of the tumor cells (31). Blockade of PD-1/PD-L1 signaling with checkpoint inhibiting antibodies has been shown to promote antitumor T-cell functionality (32). Efficacy of immunotherapies is likely related to the expression of the corresponding targets in the selected patient population (33,34), which should be considered as a patient selection criterion for such clinical trials in future. However, for PD-1/PD-L1 expression this dependence may not always be true (8,21).

Incidence of moderate adverse effects such as anorexia, abdominal pain, nausea, vomiting and fever appeared to be similar in chemotherapy and immunotherapy groups. But incidence of fatigue in immunotherapy receiving patients is less, suggesting an important beneficial effect by this therapy in improving the quality of life of patients. Also, the number of patients with anemia and neutropenia are less in immunotherapy group indicating a less secondary aggravated effect on hematological parameters. It has been recognized that chemotherapy and chemoradiotherapy in the treatment of NSCLC have adverse effects on bone marrow, leading to anemia, neutropenia and also thrombocytopenia (35). It is possible that immunotherapy assisted antitumor effects are helpful in strengthening the normal cellular homeostatic mechanisms and in overcoming the toxic side effects of chemotherapy. Better hematological parameters are likely further improve the general health and the daily living ability of the patient. Immunotherapy was earlier shown to be safe for agents that trigger specific antitumor reaction (36,37). Thus, overall immunotherapies are safe and well tolerated and when combined with chemotherapy, they are somewhat protective against the toxic effects of chemotherapeutics, particularly on blood parameters. In as much as exercise also has beneficial effects in reducing the risk of lung cancer (5), it is of interest to assess whether a combination of immunotherapy with medium level of supervised exercise has any added benefit to the lung cancer patients, who are at 0–1 score for ECOG performance.

A major limitation of the present meta-analysis is the smaller number of included studies in vaccine-based immunotherapy group. Even though we combined both Mab-based therapies and vaccine-based therapies for comparison against chemotherapy controls for getting a larger picture of the effectiveness of immunotherapy, ideal comparison would be separate comparisons for these two types of immunotherapies. This was done for analyzing the effects on PFS and OS, where we noticed specific effects on PFS. Another limitation is that we included one Mab-based therapy study that targeted VEGF (28), instead of a direct tumor specific antigen, we included this study, as VEGF is important for neovascularization of the tumors and for tumor growth and is secreted by tumor cells. Another important limitation is the different treatment durations of the included studies, as this could have influenced the observed PFS and OS. In as much as female patients with NSCLC are known to have better survival and as it has been seen in the present study that in all the included studies there is a higher preponderance of males, it is important to separate males from females when analyzing the beneficiary effects of immunotherapy. This could not be done due to unavailability of individual patient data for all the included studies. Future analyses should take this into consideration to assess if males or females show a different/better response to a given treatment.

In conclusion, immunotherapy of NSCLC is beneficial and shows better efficacy than chemotherapy/placebo in improving PFS and OS. Besides, immunotherapies, due to their less adverse effects, seem to have beneficial impact on the quality of life of patients and the daily living ability.

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August-2017
Volume 14 Issue 2

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Online ISSN:1792-1082

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Spandidos Publications style
Yu DP, Cheng X, Liu ZD and Xu SF: Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: Meta-analysis and systematic review. Oncol Lett 14: 1568-1580, 2017
APA
Yu, D., Cheng, X., Liu, Z., & Xu, S. (2017). Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: Meta-analysis and systematic review. Oncology Letters, 14, 1568-1580. https://doi.org/10.3892/ol.2017.6274
MLA
Yu, D., Cheng, X., Liu, Z., Xu, S."Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: Meta-analysis and systematic review". Oncology Letters 14.2 (2017): 1568-1580.
Chicago
Yu, D., Cheng, X., Liu, Z., Xu, S."Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: Meta-analysis and systematic review". Oncology Letters 14, no. 2 (2017): 1568-1580. https://doi.org/10.3892/ol.2017.6274